Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][C@@H:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[O:14])[CH2:11][C@@H:10]([CH:15]([CH3:17])[CH3:16])[C@@H:9]1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H](CO)N2C(=O)OC(C)(C)C)ccc1OC
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COCCCOc1cc([C@H]2[C@H](C(C)C)C[C@@H](C=O)N2C(=O)OC(C)(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Using SO3/pyridine complex: A solution of 4.7 g of alcohol 6 in 58 ml of methylene chloride is treated with 33 mL of dimethylsulphoxide and 5.67 g of triethylamine is added. The mixture is cooled to 0° C. and a solution of 6.84 g of the SO3/pyridine complex dissolved in 46 mL of dimethyl sulphoxide is added dropwise within 20 minutes. The reaction is stirred at 0° C. for 2 hours and quenched with 105 mL of water and 105 mL of heptane. The organic layer is separated and washed with 25 mL of 10% aqueous sodium hydrogen sulphate solution. The organic phase is then washed with 110 mL of water followed by 25 mL of saturated aqueous sodium hydrogen carbonate solution. Finally the organic phase is washed with water until the pH of the aqueous solution is 7. The solvent is then removed to give the aldehyde 7 as an oil. A negative [a]d is found at c=1, CHCl3. 1H-NMR (d6-DMSO, 300K) 9.75 (1H), 6.90-6.80 (3H), 4.63-4.30 (3H), 4.00 (2H), 3.75 (3H), 3.50 (3H), 3.23 (3H), 2.10-1.90 (4H), 1.85 (1H), 1.60 (1H), 1.05 (9H), 0.85 (6H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C@H:11]1[N:16](C(OC(C)(C)C)=O)[CH2:15][C@@H:14]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:53])[C@H:34]([CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[NH:35][C:36]([O:38][CH3:39])=[O:37])[O:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58]>>[CH2:1]([NH:8][C:9]([C@H:11]1[NH:16][CH2:15][C@@H:14]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:53])[C@H:34]([CH:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[NH:35][C:36]([O:38][CH3:39])=[O:37])[O:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[C:57]([OH:63])([C:59]([F:62])([F:61])[F:60])=[O:58]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)NCc2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN[C@H](C(=O)NCc2ccccc2)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl (2R,5S)-5-(benzylcarbamoyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate in a 1:1 mixture of CH2Cl2/TFA (0.1 M) was stirred at rt for 1 hr. The reaction mixture was concentrated under reduced pressure and the residue was co-evaporated twice with heptane and triturated in Et2O to afford the desired product as a TFA salt. Alternatively, the TFA salt, after concentration, could be neutralized with aqueous saturated NaHCO3, extracted with EtOAc, dried over Na2SO4, filtered and concentrated and then purified by automated SiO2 flash chromatography system using solvent gradient of 0% to 10% MeOH/CH2Cl2 to afford the desired compound. Alternatively, the free base could be purified by filtration on SCX SPE cartridge made of pTSA-SiO2 eluted first with MeOH to remove non basic impurities and eluted then with 10% NH4OH/MeOH to elute the free base and afford the desired compound after concentration under reduced pressure.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][C:8](=[O:24])[C@@H:9]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=1)[CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:6])[CH:2]=[CH2:3].B.C(=O)(O)[O-:27].[Na+].OO>O1CCCC1.C(O)C>[CH:11]1([CH2:10][C@H:9]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[C:8]([NH:7][C:5]([NH:4][CH2:1][CH:2]([OH:27])[CH3:3])=[O:6])=[O:24])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C([O-])O
Reactant: C=CCNC(=O)NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(O)CNC(=O)NC(=O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 11 %

Procedure:
A solution of 1-allyl-3-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-urea (prepared in Example 24, 765 mg, 2.07 mmol) in tetrahydrofuran (50 mL) cooled to 0° C. was treated with a 1.0M borane solution in tetrahydrofuran (4.14 mL, 4.14 mmol). The reaction was allowed to warm from 0° C. to 25° C. over 1 h. At this time, the reaction was re-cooled to 0° C. and treated with ethanol (15 mL) followed by a mixture of a saturated aqueous sodium bicarbonate solution (45 mL) and hydrogen peroxide (15 mL). The resulting mixture was allowed to warm from 0° C. to 25° C. over 1 h. The reaction was then slowly quenched with a saturated aqueous sodium sulfite solution and then extracted with ethyl acetate (3×30 mL). The organics were washed with a saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 1-[3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl]-3-(2-hydroxy-propyl)-urea (103 mg, 11%) as a white foam: [α]23589=−33.0° (c=0.094, chloroform); EI-HRMS m/e calcd for C18H24Cl2N2O3 (M+) 386.1164, found 386.1151.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16]S(C3C=C(C)OC=3C)(=O)=O)[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:29][N:30]1[CH:34]=[C:33]([S:35](Cl)(=[O:37])=[O:36])[C:32]([C:39]([F:42])([F:41])[F:40])=[N:31]1.FC1C=CC(OC)=C(C2C=CC(C(N)C)=CC=2)C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]([NH:16][S:35]([C:33]3[C:32]([C:39]([F:42])([F:41])[F:40])=[N:31][N:30]([CH3:29])[CH:34]=3)(=[O:37])=[O:36])[CH3:15])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cc(C)oc2C)cc1
Reactant: Cn1cc(S(=O)(=O)Cl)c(C(F)(F)F)n1
Agent: COc1ccc(F)cc1-c1ccc(C(C)N)cc1
Product: COc1ccc(F)cc1-c1ccc([C@@H](C)NS(=O)(=O)c2cn(C)nc2C(F)(F)F)cc1

Procedure:
Prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) starting with 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-sulfonyl chloride and 1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 7.40, 7.16 (a/b, 4H), 7.05-6.88 (m, 3H), 4.89 (m, 1H), 4.60 (t, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 1.52 (d, 3H) ppm; MS (ESI) m/z: 480 [M+Na]+.
Reaction SMILES: [CH:1]1([C:4]2(C(O)=O)[CH2:8][S:7][N:6]=[N:5]2)[CH2:3][CH2:2]1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[CH3:36])[NH2:32].C1C[O:40][CH2:39]C1>O>[Cl:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][C:35]=1[CH3:36])[NH:32][C:39]([C:8]1[S:7][N:6]=[N:5][C:4]=1[CH:1]1[CH2:2][CH2:3]1)=[O:40]
Reactant: O=C(O)C1(C2CC2)CSN=N1
Reactant: Cc1ccc(N)cc1Cl
Reactant: C1CCOC1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc(NC(=O)c2snnc2C2CC2)cc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 99 %

Procedure:
4-Cyclopropyl-1,2,3-thiadiazolecarboxylic acid (4 g; 24 mmols), 2-chloro-1-methylpyridinium iodide (7.2 g; 28 mmols), triethylamine (5.9 g; 58 mmols) and 3-chloro-4-methylaniline (3.7 g; 26 mmols) were dissolved or suspended in THF (50 ml), followed by stirring at room temperature for 10 hours. Water was added thereto to stop the reaction, the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to thereby obtain 6.9 g of 3′-chloro-4-cyclopropyl-4′-methyl-1,2,3-thiadiazole-5-carboxanilide.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][C:3]=1/[CH:11]=[CH:12]/[C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([O:22][CH3:23])=[CH:17][CH:16]=2.Br[CH2:25][CH2:26][O:27]C1CCCCO1.[C:34]1(=[O:40])[NH:38][C:37](=[O:39])[CH:36]=[CH:35]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[OH:27][CH2:26][CH2:25][N:14]1[C:13]2[CH:12]=[C:11]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=3)[C:35]3[C:34](=[O:40])[NH:38][C:37](=[O:39])[C:36]=3[C:21]=2[C:20]2[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:15]1=2
Reactant: BrCCOC1CCCCO1
Reactant: O=C1C=CC(=O)N1
Reactant: COc1ccc2[nH]c(/C=C/c3ccc([N+](=O)[O-])cc3Br)cc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)c1c3c(c(-c4ccccc4)cc1n2CCO)C(=O)NC3=O
Temperature: 50 °C

Procedure:
5-methoxy-2-[(E,Z)-2-phenylethenyl]-1H-indole (II; Ar=phenyl) (1.93 g, 7.74 mmol was reacted with 2-(2-bromoethoxy)tetrahydro-2H-pyran using the procedure described in example 38. This material was reacted directly with maleimide (0.79 g) using the procedure described in method 4. The product obtained was reacted using the procedure described in example 70 gave crude material that was then dissolved in methanol (100 mL) to which p-toluenesulfonic acid (30 mg) was added before the solution was warmed to 50° C. for 3h. The solution was then diluted with water and extracted with ethyl acetate. The organic phase was dried, the drying agent was removed and the solution was concentrated to dryness before being adsorbed onto silica and chromatographed eluting with ethyl acetate/hexane (1:2 to 1:1) to give 6-(2-Hydroxyethyl)-9-methoxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=phenyl, R10═(CH2)2OH) (201) in a yield of 0.51 g, 17% as a yellow powder; mp 262–264° C. 1H NMR δ [(CD3)2SO] 11.09 (br s, 1H), 8.56 (d, J=2.6 Hz, 1H), 7.83 (s, 1H), 7.66 (m, 3H), 7.47 (m, 3H), 7.28 (dd, J=9.0, 2.6 Hz, 1H), 4.86 (t, J=5.5 Hz, 1H), 4.55 (t, J=5.3 Hz, 2H), 3.90 (s, 3H), 3.78 (m, 2H). Found: C, 71.47; H. 4.77; N, 7.32. C23H18N2O4 requires: C, 71.49; H, 4.70; N, 7.25.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6]C=CC=1.C1(CN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CC1.[NH2:42][CH2:43][C:44]1[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=1>>[CH:2]1([CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:42][CH2:43][C:44]4[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:7][CH2:6]1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 33 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine in place of benzylamine, the title compound was obtained as a white powder in 33% yield: mp 157-158° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.53-8.47 (m, 2H), 8.42-8.40 (m, 1H), 7.68-7.64 (m, 1H), 7.33-7.29 (m, 1H), 4.34 (d, J=5.7 Hz, 2H), 3.99 (t, J=7.2 Hz, 2H), 3.61 (t, J=7.2 Hz, 2H), 3.05 (d, J=6.9 Hz, 2H), 2.43 (s, 3H), 1.03-0.88 (m, 1H), 0.53-0.37 (m, 2H), 0.25-0.12 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 162.3, 157.9, 155.2, 151.7, 149.3, 148.5, 135.6, 135.5, 123.9, 117.7, 48.2, 42.5, 42.3, 41.5, 17.6, 9.3, 3.6; MS (ES+) m/z 372.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:19]([CH2:20]I)[CH2:18][C:17]3[C:22]4[C:9]2=[N:10][CH:11]=[N:12][C:13]=4[CH:14]=[C:15]([O:25][CH3:26])[C:16]=3[O:23][CH3:24])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:19]([CH3:20])=[CH:18][C:17]3[C:22]4[C:9]2=[N:10][CH:11]=[N:12][C:13]=4[CH:14]=[C:15]([O:25][CH3:26])[C:16]=3[O:23][CH3:24])=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc3c2c(c1OC)CC(CI)N3c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc3c2c(c1OC)C=C(C)N3c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
To a solution of 4-(4-chloro-phenyl)-5-iodomethyl-7,8-dimethoxy-5,6-dihydro-4H-1,3,4-triaza-phenal (0.15 g, 0.31 mmol) (from Example 16, Step F, supra) in toluene (50 mL) was added DBU (0.46 mL, 3.1 mmol) (Fluka). The reaction mixture was heated at 120° C. for 1 hour. The mixture was then diluted with chloroform (100 mL), and washed with H2O. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:1:0.05) as eluent to give the desired 4-(4-chloro-phenyl)-7,8-dimethoxy-5-methyl-4H-1,3,4-triaza-phenalene as a pale yellow solid. (Yield 0.1 g, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([CH3:15])[N+:9]=1[O-])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18].C(N(CC)CC)C.[Cl:36]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([C:8]1([C:24](=[O:25])[C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:28][CH:27]=2)[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([CH2:15][Cl:36])[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N)c(C(=O)OC(C)(C)C)[n+]1[O-]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C1(C(=O)c2ccc([N+](=O)[O-])cc2)NC(CCl)=CC=C1N
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
1 ml of a chloroform solution containing 0.22 g (1.0 mmol) of 2-t-butoxycarbonyl amino-6-methyl pyridine-N-oxide was added dropwise to 5 mL of a chloroform solution containing 2.0 mmol of para-nitrobenzoyl chloride over 10 minutes at room temperature. After 20 minutes had elapsed therefrom, the reaction mixture was cooled to −15° C., and 0.30 g (3.0 mmol) of triethylamine was added dropwise thereto over 5 minutes. After 5 minutes had elapsed therefrom, 1 ml of a chloroform solution containing 0.20 g (0.67 mmol) of triphosgene was added dropwise thereto over a period of 5 minutes. After 20 minutes had elapsed therefrom, 0.20 g (2.0 mmol) of triethylamine was added dropwise thereto over 5 minutes, and the resulting mixture was then stirred for 30 minutes. The resulting reaction solution was poured into saturated sodium bicarbonate water, and was extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated. The resulting crude product was purified by column chromatography (hexane/ethyl acetate) to obtain 2-t-butoxycarbonyl-2-para-nitrobenzoyl amino-6-chloromethyl pyridine which was the target product with a yield of 64% (as measured by HPLC).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.C(O)(=O)C.C([BH3-])#N.[Na+]>O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 61.2 %

Procedure:
To a chilled mixture of ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate (26 g), ethanol (40 ml) and acetic acid (6.2 g) is added sodium cyanoborohydride (4.4 g) with stirring. After being stirred for 1 hour, the mixture is allowed to stand overnight at room temperature, diluted with water (500 ml) and extracted with methylene chloride. The extract is dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel column chromatography using hexane-ethyl acetate (2:1) as an eluent to yield ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate (16 g) as a colorless oil.
Reaction SMILES: [C:1](=O)([O-])[O-].[Na+].[Na+].S(OC)(OC)(=O)=O.[OH:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[O:18][C:17](=[O:25])[CH:16]=1>CC(C)=O>[CH3:1][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[O:18][C:17](=[O:25])[CH:16]=1
Reactant: O=c1cc(O)cc(C(F)(F)F)o1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1cc(C(F)(F)F)oc(=O)c1
Yield: 107.7 %

Procedure:
Sodium carbonate (1.35 g, 13 mmol) and dimethyl sulfate (2.17 g, 17 mmol) were added to a solution of 4-hydroxy-6-trifluoromethylpyran-2-one (3.0 g, 17 mmol) in acetone (50 mL). The mixture was heated under reflux for 3 hours and, after cooling, filtered. Concentration of the filtrate resulted in 2.9 g of crude product as a brown oil. It was possible to obtain 4-methoxy-6-trifluoromethylpyran-2-one (2.74 g, 14 mmol, 83%) as colorless needles with a melting point of 61° C. by crystallization from hexane.
Reaction SMILES: [Na].[CH3:2][O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5].Cl.Cl[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>CO>[CH3:2][O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([O:15][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5]
Reactant: COC(=O)c1cc2cccc(O)c2o1
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)c1cc2cccc(OCc3cccnc3)c2o1
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
Sodium (0.37 g.) was dissolved in methanol (70 ml.) and 7-hydroxybenzofuran-2-carboxylic acid methyl ester (1.54 g.) was added. The solution was stirred for 15 minutes ad then 3-chloromethylpyridine hydrochloride (1.32 g.) was added. The mixture was heated under reflux for 8 hours and then evaporated. Water was added to the residue and the mixture was extracted sevral times with ethyl acetate. The combined extracts were washed with water and dried (Na2SO4). Evaporation of the solvent gave a solid which was chromatographed on silica gel. Elution with chloroform gave a solid which was crystallized from methanol/water to give 7-(3-pyridylmethoxy)benzofuran-2-carboxylic acid methyl ester (1.0 g.), m.p. 117°-118° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][CH:11]([C:13]([O:15][CH3:16])=[O:14])[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1.[CH2:21]1CCN2C(=NCCC2)CC1.BrC(Cl)(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:21])=[O:14])[N:12]=2)=[C:4]([NH:17][CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: COC(=O)C1COC(c2cnc(Cl)cc2NC(C)C)=N1
Reactant: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)(Cl)Br
Solvent: ClCCl
Product: CCOC(=O)c1coc(-c2cnc(Cl)cc2NC(C)C)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)-4,5-dihydrooxazole-4-carboxylate (37) (100 mg, 0.336 mmol) in DCM (20 mL), DBU (1.008 mmol) and bromotrichloromethane (0.403 mmol) were added at 0° C. and stirred the reaction mixture for 2 h at 0° C. Reaction temperature was raised to room temperature and stirred the reaction for 10 min. The reaction mixture was diluted with DCM and washed with water, 10% NaHCO3 solution and brine solution. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by flash chromatography using silica gel and EtOAC:pet ether as eluent to afford the title compound, ethyl 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)oxazole-4-carboxylate (38). 1H NMR: 400 MHz, DMSO-d6: δ 1.24-1.27 (m, 6H), 3.87 (s, 3H), 3.92-3.97 (m, 1H), 6.92 (s, 1H), 8.36 (d, J=7.60 Hz, 1H), 8.60 (s, 1H), 9.00 (s, 1H).
Reaction SMILES: CC(C1C=C(C(C)C)C=C(C(C)C)C=1S(O[CH2:20][C:21]1([OH:41])[CH2:24][N:23]([C:25]([C:27]2[C:31]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=3[F:40])=[CH:30][S:29][CH:28]=2)=[O:26])[CH2:22]1)(=O)=O)C.[H-].[Na+].[C:44]([NH2:48])([CH3:47])([CH3:46])[CH3:45]>O1CCCC1>[CH3:45][C:44]([NH:48][CH2:20][C:21]1([OH:41])[CH2:24][N:23]([C:25]([C:27]2[C:31]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([I:39])=[CH:35][C:34]=3[F:40])=[CH:30][S:29][CH:28]=2)=[O:26])[CH2:22]1)([CH3:47])[CH3:46]
Reactant: CC(C)(C)N
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)OCC2(O)CN(C(=O)c3cscc3Nc3ccc(I)cc3F)C2)c(C(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)NCC1(O)CN(C(=O)c2cscc2Nc2ccc(I)cc2F)C1
Reaction time: 16 h
Yield: 11 %

Procedure:
[1-({4-[(2-Fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)-3-hydroxyazetidin-3-yl]methyl 2,4,6-tris(1-methylethyl)benzenesulfonate (101 mg, 0.141 mmol) was dissolved in tetrahydrofuran (2 mL) and was treated with sodium hydride (60 wt % dispersion in oil; 17 mg, 0.425 mmol) at ambient for 20 minutes. Tetrahydrofuran (2 mL) and tert-butylamine (0.1 mL) were added and the mixture was stirred at ambient for 16 h. The mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase HPLC and the clean fractions were combined, neutralized with saturated sodium bicarbonate solution and the organic solvent was removed in vacuo. The remaining aqueous residue was extracted twice with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 3-{[(1,1-dimethylethyl)amino]methyl}-1-({4-[(2-fluoro-4-iodophenyl)amino]-3-thienyl}carbonyl)azetidin-3-ol (8 mg, 0.016 mmol, 11% yield): 1H NMR (400 MHz, d6-DMSO): 9.64 (br, 1H), 8.08 (d, 1H), 7.59 (dd, 1H), 7.44 (dd, 1H), 7.36 (t, 1H), 7.12 (d, 1H), 4.39 (d, 1H), 4.22 (d, 1H), 4.03 (d, 1H), 3.80 (d, 1H), 2.68 (br, 2H) 1.04 (s, 9H); MS (EI) for C19H23FIN3O2S: 504 (MH+).
Reaction SMILES: N([O-])=[O:2].[Na+].N[C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.S(=O)(=O)(O)O>[OH:2][C@@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]([OH:16])=[O:15]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H](O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 14 g (217 mmol) of sodium nitrite in 20 ml of water was added dropwise to a solution of 14 g (85 mmol) of L-phenylalanine in 100 ml of 1 N sulfuric acid at 0° C. over 3 hours, and the mixture was stirred overnight at room temperature. After extraction with three 100-ml portions of ethyl acetate, the organic phase was dried over sodium sulfate. The optical purity of (2S)-2-hydroxy-3-phenylpropionic acid in this extract was 93.0% ee. The solvent was distilled off under reduced pressure to give 12 g of crude (2S)-2-hydroxy-3-phenylpropionic acid. Further, this crude product was purified by recrystallization using 35 ml of ethyl acetate to give 7.5 g (yield 53%) of the desired (2S)-2-hydroxy-3-phenylpropionic acid. The proton concentration (normality) in the reaction of this comparative example was 1.0 mol/kg, the amount of the protonic acid was 1.2 equivalents (relative to L-phenylalanine), and the reaction temperature was 0° C. to room temperature.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=2[O:2]1.Br[C:14]1[CH:18]=[CH:17][S:16][C:15]=1[S:19]([N:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1)(=[O:21])=[O:20]>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:14]3[CH:18]=[CH:17][S:16][C:15]=3[S:19]([N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)(=[O:20])=[O:21])=[CH:4][C:3]=2[O:2]1
Reactant: O=S(=O)(c1sccc1Br)n1cccc1
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: O=S(=O)(c1sccc1-c1ccc2c(c1)OCO2)n1cccc1
Yield: 90 %

Procedure:
N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole was prepared in the same manner as described in Example 32C using 3,4-methylenedioxyphenylboronic acid and N-(3-bromothiophene-2-sulfonyl)pyrrole. The crude product was purified by flash column chromatography on silica gel using 2% EtOAc in hexane as the eluent resulting in N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole in a 90% yield.